The present invention relates to novel benzene fused ring derivatives, and a thromboxane A2 (referred to as xe2x80x9cTXA2xe2x80x9d hereinafter) receptor antagonist comprising one of the compounds as an active component.
TXA2 discovered by Samuelsson et al in 1975 has strong platelet aggregating action, vascular smooth muscle contracting action and bronchial smooth muscle contracting action (Proc. Natl. Acad. Sci. U.S.A., 72, 2994 (1975)). On the other hand, as a compound having reverse actions, i.e., strong platelet aggregation inhibiting action and vascular relaxing action, prostaglandin I2 (PGI2) is known (Nature, 263, 663 (1976)). Both compounds are synthesized from arachidonic acid in vivo, and it is said that a balance between TXA2 and PGI2 greatly concerns maintenance of the homeostasis of the circulatory system because of the strong actions thereof. Therefore, with the balance shifted to the TXA2 side, phenomena such as activation of the platelets and subsequent thrombogenesis and vascular contraction occur. This is possibly a factor that causes ischemic heart diseases such as angina pectoris, myocardial infarction, etc., and circulatory diseases such as celebrovascular disorder, nephropathy, etc. It is also thought that TXA2 concerns bronchial asthma because of its strong bronchial smooth muscle contracting action. Therefore, in order to treat ischemic heart diseases such as angina pectoris, myocardial infarction, etc., circulatory diseases such as celebrovascular disorder, nephropathy, etc., or bronchial asthma or the like, it is thought to be important to return the off-balance state of TXA2 and PGI2 to the normal state, and a medicine for inhibiting the action of TXA2 or a medicine having the action as a PGI2 receptor agonist is thought to be effective to treat these diseases. As medicines for inhibiting the actions of TXA2 concerning the occurrence of the above-described diseases, TXA2 receptor antagonists have been reported so far (Circulation, 81, Suppl I, I-69 (1990), Medicinal Research Reviews, 11, 503 (1991)). However, conventional TXA2 receptor antagonists exhibit unsatisfactory clinical effects.
An object of the present invention is to provide an excellent TXA2 receptor antagonist having the action as a PGI2 receptor agonist.
The present invention provides benzene fused heterocyclic derivatives represented by the following formula (I): 
wherein
A1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR4xe2x80x94, wherein R4 is hydrogen or alkyl having 1 to 5 carbon atoms;
A2 is xe2x80x94(Nxe2x80x94)xe2x80x94CH2, xe2x80x94(Nxe2x80x94)xe2x80x94COxe2x80x94, xe2x80x94(CHxe2x80x94)xe2x80x94, or xe2x80x94(Cxe2x80x94)xe2x95x90CHxe2x80x94;
A3 is alkylene having 1 to 4 carbon atoms, alkenylene having 2 to 4 carbon atoms, or alkynylene having 2 to 4 carbon atoms;
A4 is xe2x80x94S(O)pxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR5xe2x80x94, xe2x80x94NR5COxe2x80x94, or xe2x80x94CONR5xe2x80x94, wherein R5 is hydrogen, alkyl having 1 to 5 carbon atoms, or phenyl (which may be substituted by a group or groups selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms), and p is an integer of 0 to 2;
m is an integer of 1 to 3;
R1 is xe2x80x94Xxe2x80x94(CH2)nCOOR6 wherein X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94, R6 is hydrogen, alkyl having 1 to 5 carbon atoms, or an atom or group which gives a pharmacologically acceptable salt, and n is an integer of 1 to 3;
R2 is the following:
(1) xe2x80x94Ar (wherein Ar is phenyl, naphthyl, furyl, or thienyl (wherein phenyl, naphthyl, furyl, or thienyl may be substituted by a group or groups selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms); or
(2) alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms, wherein alkyl, alkenyl, or alkynyl is substituted by one or two Ar (wherein Ar is defined as the same as the above), and may be further substituted by a group or groups selected from xe2x80x94OH, xe2x80x94CF3, and cycloallyl having 3 to 8 carbon atoms);
R3 is hydrogen, halogen, alkyl having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms: and
either or both of A1 and A2 contain a hetero atom other than carbon. The present invention also provides a TXA2 receptor antagonist containing one of the above compounds of the present invention as an active ingredient.
The compounds of the present invention have strong TXA2 receptor antagonistic action and PGI2 receptor agonistic action, and are effective as medicines for treating or preventing diseases concerning TXA2.
Of the compounds represented by the above formula (I), compounds represented by the following formula (II) are preferred. 
[wherein R1, R2, R3, A1, A2, A3, A4 and m are defined as the same as the above].
Although R1, R2, R3, R4, R5, R6, A1, A2, A3, A4, X, m, n, and Ar in formula (I) or (II) are defined as described above, these groups are described in further detail below.
R1 is xe2x80x94Xxe2x80x94(CH2)nxe2x80x94COOR6 (wherein X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94, R6 is hydrogen, alkyl having 1 to 5 carbon atoms, or an atom or group which gives a pharmacologically acceptable salt, and n is an integer of 1 to 3). X is particularly preferably xe2x80x94Oxe2x80x94, and n is preferably 1 or 2, more preferably 1.
Examples of alkyl R6 having 1 to 5 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and the like.
Examples of pharmacologically acceptable cations of R6 include metal cations, ammonium, amine cations, and quaternary ammonium cations. Preferred examples of metal cations include cations derived from alkali metals, for example, such as lithium, sodium, and potassium, alkali earth metals, for example, such as magnesium and calcium. Of course, the present invention include cations of other metals, for example, such as aluminum, zinc, and iron.
Pharmacologically acceptable amine cations are derived from primary, secondary or tertiary amines. Examples of suitable amines include methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, xcex1-phenylethylamine, xcex2-phenylethylamine, ethylenediamine, diethylenetriamine, similar aliphatic, alicyclic or heterocyclic amines having up to 18 carbon atoms, for example, such as 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrolidine, 2-methylpyrolidine, 4-dimethylpiperazine, 2-methylpiperidine, and the like, amines containing water-soluble or hydrophilic groups, for example, such as mono-, di-, or tri-ethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-(p-aminophenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephedrine, epinephrine, procaine, and the like, basic amino acids such as lysine, alginine, and the like.
R2 is preferably alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms (alkyl, alkenyl, or alkynyl is substituted by an one or two Ar (Ar is phenyl, naphthyl, furyl, or thienyl (phenyl, naphthyl, furyl, or thienyl may be substituted by a group selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms)), and may be further substituted by a group selected from xe2x80x94OH, xe2x80x94CF3, and cycloalkyl having 3 to 8 carbon atoms), more preferably alkyl having 1 to 5 carbon atoms, which is substituted by one or two Ar (Ar is defined as the same as the above). Particularly, alkyl having 1 to 5 carbon atoms, which is substituted by one or two phenyl groups (which may be substituted by a group selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms) is preferred, and alkyl having 1 to 5 carbon atoms, which is substituted by two phenyl groups (which may be substituted by a group selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms) is more preferred.
Where R2 is alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms, which is substituted by two Ar, the two Ar groups may be the same or different.
Of Ar groups, thienyl is 2-thienyl or 3-thienyl, furyl is 2-furyl or 3-furyl, and naphthyl is 1-naphthyl or 2-naphthyl.
Examples of alkyl R2 having 1 to 5 carbon atoms which is substituted by one or two Ar include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, diphenylmethyl, 1,1-diphenylethyl, 2,2-diphenylethyl, 1,3-diphenylpropyl, 3,3-diphenylpropyl, 3,3-diphenyl-2-methylpropyl, 3,3-diphenylbutyl, 1,4-diphenylbutyl, 2,4-diphenylbutyl, 3,4-diphenylbutyl, 4,4-diphenylbutyl, 4,4-diphenyl-2-methylbutyl, 4,4-diphenyl-3-methylbutyl, 4,4-diphenylpentyl, 1,5-diphenylpentyl, 4,5-diphenylpentyl, 5,5-diphenylpentyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, phenyl(2-thienyl)methyl, phenyl(2-furyl)methyl, bis(2-thienyl)methyl, bis(2-furyl)methyl, and the like.
Examples of alkenyl R2 having 2 to 5 carbon atoms which is substituted by one or two Ar include 2-phenylvinyl, 3-phenyl-2-propenyl, 2-phenyl-1-methylvinyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 2,2-diphenylvinyl, 3,3-diphenyl-2-propenyl, 3,3-diphenyl-1-propenyl, 4,4-diphenyl-3-butenyl, 1,4-diphenyl-3-butenyl, 2,4-diphenyl-3-butenyl, 3,4-diphenyl-2-butenyl, 4,4-diphenyl-2-butenyl, 4,4-diphenyl-2-methyl-3-butenyl, 4,4-diphenyl-3-methyl-3-butenyl, 5,5-diphenyl-4-pentenyl, 1,5-diphenyl-4-pentenyl, 4,5-diphenyl-3-pentenyl, 4,4-diphenyl-2-pentenyl, 3,3-bis(2-thienyl)-2-propynyl, 3,3-bis(2-furyl)-2-propynyl, 3,3-bis(1-naphthyl)-2-propynyl, and the like.
Examples of alkynyl R2 having 1 to 5 carbon atoms which is substituted by one or two Ar include 3-phenyl-2-propynyl, 4-phenyl-2-butynyl, 5-phenyl-3-pentynyl, 3,3-diphenyl-1-propynyl, 3,3-diphenyl-1-butynyl, 4,4-diphenyl-2-butynyl, 5,5-diphenyl-3-pentynyl, 4,4-bis(2-thienyl)-2-butynyl, 4,4-bis(2-furyl)-2-butynyl, 4,4-bis(1-naphthyl)-2-butynyl, and the like.
A phenyl group, a naphthyl group, a furyl group, or a thienyl group represented by Ar may be substituted by a group selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms. Preferred examples of alkyl having 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like. Preferred examples of alkoxy having 1 to 5 carbon atoms include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy, pentyloxy, and the like. Preferred examples of halogen include fluorine, chlorine, bromine, and iodine. Preferred examples of alkylamino having 1 to 5 carbon atoms include methylamino, dimethylamino, ethylamino, diethylamino, diisopropylamino, di-t-butylamino, and the like.
Examples of alkyl R3 having 1 to 5 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and the like. Examples of alkoxy having 1 to 5 carbon atoms include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy, pentyloxy, and the like. Examples of halogen include fluorine, chlorine, bromine, and iodine.
A1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR4xe2x80x94 (wherein R4 is hydrogen or alkyl having 1 to 5 carbon atoms). Examples of alkyl R4 having 1 to 5 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and the like. A1is more preferably xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94.
Examples of A2 include xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94, xe2x80x94(Nxe2x80x94)xe2x80x94COxe2x80x94, xe2x80x94(CHxe2x80x94)xe2x80x94, and xe2x80x94(CHxe2x80x94)xe2x95x90CHxe2x80x94 which are respectively represented by the following: 
A2 is more preferably xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94 or xe2x80x94(CHxe2x80x94)xe2x80x94.
Examples of alkylene A3 having 1 to 4 carbon atoms include methylene, ethylene, trimethylene, tetramethylene, and the like. Examples of alkenylene A3 having 2 to 4 carbon atoms include vinylene, propenylene, butenylene, and the like. Examples of alkynylene A3 having 2 to 4 carbon atoms include ethynylene, propynylene, butynylene, and the like. Particularly, alkylene having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene, tetramethylene or the like is preferred.
A4 is xe2x80x94S(O)pxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NR5xe2x80x94, xe2x80x94NR5COxe2x80x94, or xe2x80x94CONR5xe2x80x94 (wherein R5 is hydrogen, alkyl having 1 to 5 carbon atoms, or phenyl (which may be substituted by a group selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms), and p is an integer of 0 to 2). Examples of alkyl R5 having 1 to 5 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and the like.
Of substituents of a phenyl group R51 preferred examples of alkyl having 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like. Preferred examples of alkoxy having 1 to 5 carbon atoms include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy, pentyloxy, and the like. Preferred examples of halogen include fluorine, chlorine, bromine, and iodine. Preferred examples of alkylamino having 1 to 5 carbon atoms include methylamino, dimethylamino, ethylamino, diethylamino, diisopropylamino, di-t-butylamino, and the like.
A1 is preferably xe2x80x94S(O)pxe2x80x94 (p represents an integer of 0 to 2) or xe2x80x94Oxe2x80x94, more preferably xe2x80x94S(O)pxe2x80x94 (p represents an integer of 0 to 2).
m is an integer of 1 to 3, preferably 1 or 2, more preferably 1.
Although some compounds represented by the above formula (I) have asymmetric carbon and geometric isomers, the formula (I) of the present invention includes all possible stereo isomers and geometric isomers.
Although some examples of the compounds of the present invention are listed below, the present invention is not limited to these examples.
(1-(4,4-diphenylbutyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(4,4-diphenylpentyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(diphenylmethoxy)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(1,1-diphenylethoxy)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(benzylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(1-phenyl-1-methylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(3-(diphenylmethylthio)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(3-(1,1-diphenylethylthio)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(2,2-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(2,2-diphenylpropylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(2,2,2-trifluoro-1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(diphenylmethylsulfinyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(1,1-diphenylethylsulfinyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(diphenylmethylsulfonyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(1,1-diphenylethylsulfonyl)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(3-diphenylamino-3-oxopropyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(4-diphenylamino-3-oxobutyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-((diphenylmethyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-((1,1-diphenylethyl)amino)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(2-(diphenylamino)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(3-(diphenylamino)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(1-(4-(diphenylamino)butyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
3-(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)propionic acid
4-(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)butyric acid
3-(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)propionic acid
4-(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yl)butyric acid
(1-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetic acid
(1-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetic acid
(2-oxo-1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(2-oxo-1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)acetic acid
(2-oxo-1-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetic acid
(2-oxo-1-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetic acid
(4-(4,4-diphenylbutyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(4,4-diphenylpentyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(1,1-diphenylethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(benzylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(1-phenyl-1-methylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(3-(diphenylmethylthio)propyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(3-(1,1-diphenylethylthio)propyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(2,2-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(2,2-diphenylpropylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(2,2,2,-trifluoro-l,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(diphenylmethylsulfinyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(1,1-diphenylethylsulfinyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(diphenylmethylsulfonyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(1,1-diphenylethylsulfonyl)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(3-diphenylamino-3-oxopropyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(4-diphenylamino-3-oxobutyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-((diphenylmethyl)amino)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-((1,1-diphenylethyl)amino)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(2-(diphenylamino)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(3-(diphenylamino)propyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-(4-(diphenylamino)butyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
3-(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)propionic acid
4-(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)butyric acid
3-(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)propionic acid
4-(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl)butyric acid
(5-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-9-yloxy)acetic acid
(5-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzoxazepin-9-yloxy)acetic acid
(3-oxo-4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(3-oxo-4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid
(4-oxo-5-(2-(diphenylmethylthio)ethyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-9-yloxy)acetic acid
(4-oxo-5-(2-(1,1-diphenylethylthio)ethyl)-2,3,4,5-tetrahydro-1H-1-benzoxazepin-9-yloxy)acetic acid
(4-(2-(diphenylmethylthio)ethyl)-3,4-dihydro-2H-1,4-benzothiazin-8-yloxy)acetic acid
(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzothiazin-8-yloxy)acetic acid
(1-(2-(diphenylmethylthio)ethyl)-1,2,3,4-tetrahydro-1,4-diazin-5-yloxy)acetic acid
(1-(2-(1,1-diphenylethylthio)ethyl)-1,2,3,4-tetrahydro-1,4-diazin-8-yloxy)acetic acid
(3-(4,4-diphenylbutyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(4,4-diphenylpentyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(diphenylmethoxy)ethyl)-2,3-dihydrobenzofuran-7-yloxy) acetic acid
(3-(2-(1,1-diphenylethoxy)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(benzylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(1-diphenyl-1-methylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(3-(diphenylmethylthio)propyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(3-(1,1-diphenylethylthio)propyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(2,2-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(2,2-diphenylpropylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(2,2,2-trifluoro-1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(diphenylmethylsulfinyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(1,1-diphenylethylsulfinyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(diphenylmethylsulfonyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(1,1-diphenylethylsulfonyl)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(3-diphenylamino-3-oxopropyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(4-diphenylamino-3-oxobutyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-((diphenylmethyl)amino)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-((1,1-diphenylethyl)amino)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(2-(diphenylamino)ethyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(3-(diphenylamino)propyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
(3-(4-(diphenylamino)butyl)-2,3-dihydrobenzofuran-7-yloxy)acetic acid
3-(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)propionic acid
4-(3-(2-(diphenylmethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)butyric acid
3-(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)propionic acid
4-(3-(2-(1,1-diphenylethylthio)ethyl)-2,3-dihydrobenzofuran-7-yl)butyric acid
(4-(2-(diphenylmethylthio)ethyl)-chroman-8-yloxy)acetic acid
(4-(2-(1,1-diphenylethylthio)ethyl)-chroman-8-yloxy)acetic acid
(4-(2-(diphenylmethylthio)ethyl)-2H-chromen-8-yloxy)acetic acid
(4-(2-(1,1-diphenylethylthio)ethyl)-2H-chromen-8-yloxy)acetic acid
The present invention includes methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, t-butyl esters, pentyl esters, and the like of the above compounds.
Although examples of methods of producing the compounds included in the present invention will be described below, the present invention is not limited to these examples.
Of the compounds of the present invention, compounds in which A4 is xe2x80x94Sxe2x80x94 and X is xe2x80x94Oxe2x80x94 can be synthesized by production method A. 
(wherein A1, A2, A3, R2, R3, and m are defined as the same as the above, R11 represents alkyl having 1 to 5 carbon atoms, R12 represents p-toluenesulfonyloxy, methanesulfonyloxy, chlorine, bromine, or iodine, R13 represents a metal cation such as lithium, sodium, potassium, or the like, or an amine cation such as an ammonium ion, a monoethanolammonium ion, a diethanolammonium ion, triethanolammonium ion, a N-methylgulcamium ion, an ephedrium ion, or the like, and n represents an integer of 1 to 3).
Step A-1 is the step of introducing an ester unit. This step is carried out by removing a proton of a phenolic hydroxyl group by using a base, and then reacting the product with the following compound:
Br(CH2)nCOOR11
or
Cl(CH2)nCOOR11
(wherein R11 and n are defined as the same as the above). As the base, potassium carbonate, potassium t-butoxide, potassium hydroxide, sodium hydroxide, sodium hydride, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step A-2 is the step of converting a hydroxyl group into a leaving group such as p-toluenesulfonyloxy, methanesulfonyloxy, bromine, or the like. Where R12 is p-toluenesulfonyloxy or methanesulfonyloxy, the conversion can be performed by conventional tosylation or mesylation. Namely, the step can be carried out by reaction with p-toluenesulfonyl chloride or methanesulfonyl chloride in coexistence with a base such as triethylamine, diisopropylamine, pyridine, or the like. As a solvent, THF, DME, dioxane, benzene, toluene, dichloromethane, DMF, or the like is preferably used, and a base such as pyridine or the like may be used as the solvent. The reaction temperature is selected from xe2x88x9280 to 150xc2x0 C., and is preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours. Where R12 is bromine, the conversion is carried out by reaction with a brominating agent such as triphenylphosphine+carbon tetrabromide, triphenylphosphine+N-bromosuccimide, or the like. As a solvent, THF, DME, dichloromethane, or the like is used. The reaction temperature is selected from xe2x88x9280 to 150xc2x0 C., and is preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours.
Step A-3 is the step of thioetherifying compound 3. This step is carried out by reacting compound 3 with a sodium or potassium salt of R2xe2x80x94SH (R2 is defined as the same as the above) which has previously been prepared. A sodium or potassium salt of R2xe2x80x94SH can be obtained by reacting R2xe2x80x94SH with a base such as sodium hydride, sodium carbonate, sodium t-butoxide, potassium hydride, potassium carbonate, potassium t-butoxide, or the like. As a solvent, THF, DME, DMF, or the like is used. The reaction temperature is selected from xe2x88x9280 to 150xc2x0 C., and is preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours. The step can also be carried out by adding a base such as potassium carbonate or the like to a solution mixture containing compound 3 and R2xe2x80x94SH.
Step A-4 is the step of ester hydrolysis of compound 4. Hydrolysis reaction is carried out by reacting ester 4 with a base in a solvent such as aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, or the like. As the base, a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, or the like is preferably used. The reaction temperature is selected from xe2x88x9220 to 150xc2x0 C., but a preferred reaction rate can be obtained at 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours. The hydrolysis reaction can also be carried out by reacting compound 4 with a metal salt of a thiol in DMF or DMSO.
Step A-5 is the step of forming a salt of compound 5. Reaction forming salt is carried out by reacting carboxylic acid 5 with a hydroxide of a metal cation or an amine. As a solvent, water, methanol, ethanol, tetrahydrofuran, ethyl acetate, or the like can be used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 80xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours.
Of the compounds of the present invention, compounds in which A4 is xe2x80x94S(O)pxe2x80x94 wherein p is 1, and X is xe2x80x94Oxe2x80x94 can be synthesized by production method B. 
(wherein A1 A2, A3, R2, R3, m, n, and R13 are defined as the same as the above).
Of Step B-1 is the step of oxidizing compound 5. Oxidation step is carried out by reacting sulfide 5 with an oxidizing agent. As the oxidizing agent, m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, hydrogen peroxide solution, or the like is preferably used. As a solvent, carbon tetrachloride, chloroform, dichloromethane, water, acetic acid, methanol, ethanol, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 100xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours.
Step B-2 is the step of forming a salt of compound 7. This step is carried out by the same method as step A-5.
Of the compounds of the present invention, compounds in which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94, A3 is straight chain alkyl having 2 to 4 carbon atoms, A4 is xe2x80x94Sxe2x80x94, and X is xe2x80x94Oxe2x80x94 can be produced by production method C.
Step C-1 is the step of nitrating compound 9. Nitration reaction is carried out by reacting phenol 9 with a nitrating agent. As the nitrating agent, nitric acid, acetic anhydride-nitric acid mixture, a nitric acid-sulfuric acid mixture, a trifluoroacetic anhydride -nitric acid mixture, potassium nitrate-trifluoroacetic acid, fuming nitric acid, or the like is preferably used. As a solvent, ethyl acetate, nitromethane, dimethoxyethane, acetic acid, trifluoroacetic acid, methanol, ethanol, water, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably xe2x88x9210 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours.
Step C-2 is the step of introducing an ester unit in compound 10. This step is carried out by removing a proton of a phenolic hydroxyl group by using a base, and then reacting the product with the following compound:
Br(CH2)mCOOR14
or
Cl(CH2)mCOOR14
(wherein R14 and m are defined as the same as the above). As the base, potassium carbonate, potassium t-butoxide, potassium hydroxide, sodium hydroxide, sodium hydride, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and usually 5 minutes to 50 hours. 
(wherein R2, R3, m, n, R11, R12, and R13 are defined as the same as the above, R14 represents alkyl having 1 to 5 carbon atoms, R15 represents alkyl having 1 to 5 carbon atoms, and q represents an integer of 1 to 3).
Step C-3 is the step of reducing and cyclizing compound 11. This step is carried out by the method of catalytically hydrogenating nitro compound 11 or the method of reducing it with a metal reducing agent. The catalytic hydrogenation preferably uses hydrogen gas, formic acid, ammonium formate, sodium formate, or the like as a hydrogen source, and palladium carbon, platinum, platinum oxide, platinum carbon, palladium acetate, a tetrakistriphenylphosphine palladium complex, or the like as a catalyst. As a reaction additive, hydrochloric acid, sulfuric acid, ammonium chloride, activated carbon, iron powder, zinc powder, or the like may be used. The reduction method using the metal reducing agent preferably uses iron, zinc, tin, or the like as the reducing agent. As a solvent, ethyl acetate, acetic acid, trifluoroacetic acid, methanol, ethanol, water, tetrahydrofuran, dimethoxyethane, or the like is preferably used. As a reaction additive, hydrochloric acid, sulfuric acid, ammonium chloride, activated carbon, an iron powder, a zinc powder, or the like may be further used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 120xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours. Where R3 is bromine, in some cases, the use of the catalytic hydrogenation method as the reduction method occurs conversion of bromine in R3 into hydrogen.
Step C-4 is the step of introducing an ester unit in compound 12. This step is carried out by removing a proton of amido by using a base, and then reacting the product with the following compound:
Br(CH2)qCOOR15
or
Cl(CH2)qCOOR15
(wherein R15 and q are defined as the same as the above). As the base, potassium carbonate, potassium t-butoxide, potassium hydroxide, sodium hydroxide, sodium hydride, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step C-5 is the step of reducing ester and amido of compound 13. The reduction is carried out by reacting compound 13 with a reducing agent. As the reducing agent, borane, a borane-tetrahydrofuran complex, a borane-dimethylsulfide complex, a sodium borohydride-boron trifluoride ether complex, a sodium borohydride-boron trifluoride tetrahydrofuran complex, or the like is preferably used. As a solvent, tetrahydrofuran, dimethoxyethane, or the like is preferably used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 120xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours.
Step C-6 is the step of demethylating compound 14. This step is carried out by reacting methyl ether 14 with a Lewis acid or protonic acid. As a Lewis acid, boron tribromide, boron trifluoride, boron trichloride, aluminum chloride, aluminum bromide, iron chloride, iron bromide, zinc chloride, phosphorus tribromide, or the like is preferably used. As a protonic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, trifluoromethansulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid-lithium chloride, hydrobromic acid-lithium bromide, or the like is preferably used. As a solvent, dichloromethane, chloroform, carbon tetrachloride, water, or the like is preferably used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably xe2x88x9210 to 120xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours.
Step C-7 is the step of introducing an ester unit into compound 15. This step is carried out by the same method as step A-1.
Step C-8 is the step of converting a hydroxyl group of compound 16 to a leaving group. This step is carried out by the same method as step A-2.
Step C-9 is the step of thioetherifying compound 17. This step is carried out by the same method as step A-3.
Step C-10 is the step of ester hydrolysis of compound 18. This step is carried out by the same method as step A-4.
Step C-11 is the step of forming a salt of compound 19. This step is carried out by the same method as step A-5.
If Of the compounds of the present invention, compounds in which A2 is xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94 and X is xe2x80x94Oxe2x80x94 can be produced by production method D. 
(wherein A1, A3, A4, R2, R3, m, n, R11, R12 and R13 are defined as the same as the above).
Step D-1 is the step of protecting a phenolic hydroxyl group by an acetyl group. This step is carried out by reacting phenol 21 with acetic anhydride or acetyl chloride in the presence of an appropriate base. As the base, pyridine, triethylamine, or the like is used. As a solvent, THF, DME, benzene, toluene, or the like is used, and pyridine may be used as the solvent. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step D-2 is the step of alkylating amido. Alkylation is carried out by reacting compound 22 with a base, and then reacting the product with the following compound:
R2xe2x80x94A3xe2x80x94A4xe2x80x94R2
(wherein R2, R12, A3 and A4 are defined as the same as the above). As the base, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step D-3 is the step of reducing amido. This step is carried out by bubbling diborane through a solution of compound 23, or adding a borane-THF solution thereto. As a solvent, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step D-4 is the step of removing an acetyl group. This step is carried out by dissolving compound 24 in methanol, ethanol, or the like, and then adding an appropriate base to the resultant solution. As the base, potassium carbonate, sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, or the like is preferably used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute. to 80 hours, and is usually 5 minutes to 30 hours.
Step D-5 is the step of introducing an ester unit into compound 25. This step is carried out by the same method as step A-1.
Step D-6 is the step of ester hydrolysis of compound 26. This step is carried out by the same method as step A-4.
Step D-7 is the step of forming a salt of compound 27. This step is carried out by the same method as step A-5.
Of the compounds of the present invention, compounds in which A2 is xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94, A3 is straight chain alkylene having 2 to 4 carbon atoms, A4 is xe2x80x94Sxe2x80x94, and X is xe2x80x94Oxe2x80x94 can be synthesized by production method E. 
(wherein A1, R2, R3, m, R11, and R13 are defined as the same as the above, R16 represents chlorine, bromine, or iodine, r represents an integer of 1 to 3, and TBS represents a t-butyldimethylsilyl group).
Step E-1 is the step of acylating compound 29. This step is carried out by reacting compound 29 with the following acid chloride in the presence of an appropriate base:
R16(CH2)rCOCl
(wherein R16 and r are defined as the same as the above). As the base, pyridine, triethylamine, or the like is used. As a solvent, methylene chloride, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9280 to 150xc2x0 C., and is preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours. This step can also be carried out by reacting compound 29 with the following acid anhydride in the presence of an appropriate base:
(R16(CH2)rCO)2O
(wherein R16 and r are defined as the same as the above) . As a solvent, methylene chloride, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step E-2 is the step of thioetherifying compound 30. This step is carried out by reacting compound 30 with a sodium or potassium salt of R2xe2x80x94SH (R2 is defined as the same as the above) which has previously been prepared. The sodium or potassium salt of R2xe2x80x94SH can be obtained by reacting R2xe2x80x94SH with a base such as sodium hydride, sodium carbonate, sodium t-butoxide, potassium hydride, potassium carbonate, potassium t-butoxide, or the like. As a solvent, THF, DME, DMF, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably xe2x88x9220 to 100xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours. The step can also be carried out by adding a base such as potassium carbonate or the like to a solution of a mixture containing compound 30 and R2xe2x80x94SH. In this step, a t-butyldimethylsilyl group is simultaneously removed.
Step E-3 is the step of reducing amido of compound 31. This step is carried out by the same method as step D-3.
Step E-4 is the step of introducing an ester unit into compound 32. This step is carried out by the same method as step A-1.
Step E-5 is the step of ester hydrolysis of compound 33. This step is carried out by the same method as step A-4.
Step E-6 is the step of forming a salt of compound 34. This step is carried out by the same method as step A-5.
Of the compounds of the present invention, compounds in which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94, A3 is straight chain alkylene having 1 to 4 carbon atoms, R3 is hydrogen, and X is xe2x80x94Oxe2x80x94 can be produced by production method F. 
(wherein R2, m, n, R11, R12, R13 and R16 are defined as the same as the above, s represents an integer of 1 to 4, and THP represents a tetrahydropyranyl group).
Step F-1 is the step of acylating methoxyaniline. This step is carried out by reacting compound 36 with the following acid chloride in the presence of an appropriate base:
R16(CH2)mCOCl
(wherein R16 and m are defined as the same as the above). As the base, pyridine, triethylamine, or the like is used. As a solvent, methylene chloride, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9280 to 150xc2x0 C., and is preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours. This step can also be carried out by reacting compound 36 with the following acid anhydride in the presence of an appropriate base:
(R16(CH2)mCO)2O
(wherein R16 and m are defined as the same as the above). As a solvent, methylene chloride, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step F-2 is the step of demethylating compound 37. This step is carried out by reacting compound 37 with boron tribromide or boron tribromide-dimethylsulfide complex. As a solvent, methylene chloride, chloroform, carbon tetrachloride, or the like is used. The reaction temperature is selected from xe2x88x92100 to 100xc2x0 C., and is preferably xe2x88x9280xc2x0 C. to the reflux temperature of the solvent. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step F-3 is the step of cyclizing compound 38. This step is carried out by reacting compound 38 with an appropriate base. As the base, potassium carbonate, potassium t-butoxide, or the like is used. As a solvent, THF, DME, DMF, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step F-4 is the step of protecting a phenol compound by tetrahydropyranyl ether. This step is carried out by reacting compound 39 with dihydropyrane in the presence of an appropriate acid catalyst. As an acid catalyst, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, or the like is used. As a solvent, THF, DME, DMF, methylene chloride, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step F-5 is the step of alkylating amide. This step is carried out by reacting compound 40 with a base, and then reacting the product with the following compound:
Br (CH2)sOTHP
or
Cl(CH2)sOTHP
(wherein s and THP are defined as the same as the above). As the base, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step F-6 is the step of reducing amide of compound 41. This step is carried out by the same method as step D-3.
Step F-7 is the step of removing a tetrahydropyranyl group of compound 42. This step is carried out by treating compound 42 with an appropriate acid catalyst. As the acid catalyst, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrochloric acid, or the like is used. As a solvent, methanol, ethanol, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step F-8 is the step of introducing an ester unit into compound 43. This step is carried out by the same method as step A-1.
Step F-9 is the step of converting a hydroxyl group of compound 44 to a leaving group. This step is carried out by the same method as step A-2.
Step F-10 is the step of thioetherifying compound 45. This step is carried out by the same method as step A-3.
Step F-11 is the step of ester hydrolysis of compound This step is carried out by the same method as step A-4.
Step F-12 is the step of forming a salt of compound 47. This step is carried out by the same method as step A-5.
Of the compounds of the present invention, compounds in a which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(Nxe2x80x94)xe2x80x94COxe2x80x94, A3 is straight chain alkylene having 1 to 4 carbon atoms, A4 is xe2x80x94Sxe2x80x94, R3 is hydrogen, and X is xe2x80x94Oxe2x80x94 can be produced by production method G. 
(wherein R2, m, n, S, R11, R12, and R13 are defined as the same as the above, and THP represents a tetrahydropyranyl group).
Step G-1 is the step of removing a tetrahydropyranyl group of compound 41. This step is carried out by the same method as step F-7.
Step G-2 is the step of introducing an ester unit into compound 49. This step is carried out by the same method as step A-1.
Step G-3 is the step of converting a hydroxyl group of compound 50 to a leaving group. This step is carried out by the same method as step A-2.
Step G-4 is the step of thioetherifying compound 51. This step is carried out by the same method as step A-3.
Step G-5 is the step of ester hydrolysis of compound 52. This step is carried out by the same method as step A-4.
Step G-6 is the step of forming a salt of compound 53. This step is carried out by the same method as step A-5.
Of the compounds of the present invention, compounds in which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(Nxe2x80x94)xe2x80x94COxe2x80x94, A3 is straight chain alkylene having 1 to 4 carbon atoms, R3 is hydrogen, and X is xe2x80x94Oxe2x80x94 can be produced by production method H. 
(wherein R2, m, n, s, R11, and R13 are defined as the same as the above, and THP represents a tetrahydropyranyl group).
Step H-1 comprises the step of alkylating amide of compound 40, and the step of removing a tetrahydropyranyl group. The step of alkylating amide is carried out by reacting compound 40 with a base, and then reacting the product with the following compound:
R12xe2x80x94(CH2)sxe2x80x94Axe2x80x94R2
(wherein R2, R12, A4, s are defined as the same as the above) As the base, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours. The step of removing a tetrahydropyranyl group is carried out by the same method as step F-7.
Step H-2 is the step of introducing an ester unit into compound 55. This step is carried out by the same method as step A-1.
Step H-3 is the step of ester hydrolysis of compound 56. This step is carried out by the same method as step A-4.
Step H-4 is the step of forming a salt of compound 57. This step is carried out by the same method as step A-5.
Of the compounds of the present invention, compounds in which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(Nxe2x80x94)xe2x80x94COxe2x80x94, A3 is straight chain alkylene having 1 to 4 carbon atoms, A4 is xe2x80x94Sxe2x80x94, R3 is hydrogen, X is xe2x80x94CH2xe2x80x94, and n is 1 can be produced by production method I. 
(wherein R2, m, s, R11, R12, and R13 are defined as the same as the above, and THP represents a tetrahydropyranyl group).
Step I-1 is the step of alkylating amide of compound 40. This step of alkylating amide is carried out by reacting compound 40 with a base, and then reacting the product with the following compound:
R12xe2x80x94(CH2)sxe2x80x94Oxe2x80x94CH2xe2x80x94Ph
(wherein R12 and s are defined as the same as the above). As the base, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step I-2 is the step of removing a tetrahydropyranyl group of compound 59. This step is carried out by the same method as step F-7.
Step I-3 is the step of trifluoromethanesulfonylating a hydroxyl group of compound 60. This step is carried out by reacting compound 60 with a trifluoromethanesulfonylating agent in the presence of a base. As the base, 2,6-lutidine, pyridine, triethylamine, diisopropylamine, diisopropylethylamine, or the like is preferably used. As the trifluoromethanesulfonylating agent, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, or the like is preferably used. As a solvent, THF, DME, dioxane, benzene, toluene, methylene chloride, DMF, or the like is used, and a base such as 2,6-lutidine, or the like may be used as the solvent. The reaction temperature is selected from xe2x88x9280 to 150xc2x0 C., and is preferably xe2x88x9220 to 50xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours.
Step I-4 is the step of introducing an ester unit into an aromatic ring of compound 61. This step is carried out by Heck reaction of compound 61 and an acrylate. As a catalyst, palladium acetate, tetrakistriphenylphosphine palladium complex, or the like is preferably used. As a reaction additive, triphenylphosphine, tris(2-methylphenyl)phosphine, lithium chloride, or the like is preferably used. As the base, 2,6-lutidine, pyridine, triethylamine, diisopropylamine, diisopropylethylamine, or the like is preferably used. As a solvent, THF, DME, dioxane, benzene, toluene, methylene chloride, DMF, or the like is used, and a base such as pyridine or the like may be used as the solvent. The reaction temperature is selected from xe2x88x9280 to 150xc2x0 C., and is preferably 0 to 120xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours.
Step I-5 is the step of reducing compound 62, comprising simultaneously reducing a double bond and reductively removing a benzyl group. This step is carried out by reducing compound 62 by a catalytic hydrogenation method. As a hydrogen source, hydrogen gas, formic acid, ammonium formate, sodium formate, or the like is preferably used. As a catalyst, palladium carbon, platinum, platinum oxide, platinum carbon, palladium acetate, a tetrakistriphenylphosphine palladium complex, or the like is preferably used. As a solvent, methanol, ethanol, ethyl acetate, acetic acid, trifluoroacetic acid, water, tetrahydrofuran, dimethoxyethane, or the like is preferably used. As a reaction additive, hydrochloric acid, sulfuric acid, activated carbon, iron powder, zinc powder, or the like is preferably further used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 120xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours.
Step I-6 is the step of converting a hydroxyl group of compound 63 to a leaving group. This step is carried out by the same method as step A-2.
Step I-7 is the step of thioetherifying compound 64. This step is carried out by the same method as step A-3.
Step I-6 is the step of ester hydrolysis of compound 65. This step is carried out by the same method as step A-4.
Step I-7 is the step of forming a salt of compound 66. This step is carried out by the same method as step A-5.
Of the compounds of the present invention, compounds in which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94, A3 is straight chain alkylene having 1 to 4 carbon atoms, A4 is xe2x80x94NHxe2x80x94, R3 is hydrogen, X is xe2x80x94Oxe2x80x94, and R2 is xe2x80x94CH2xe2x80x94R17 can be produced by production method J. 
(wherein m, s, R11, and R12 are defined as the same as the above, THP represents a tetrahydropyranyl group, and TBS represents a t-butyldimethylsilyl. R17 represents the following:
(1) -Ar (wherein Ar is phenyl, naphthyl, furyl, or thienyl (wherein phenyl, naphthyl, furyl, or thienyl may be substituted by a group selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms); or
(2) alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, or alkynyl having 2 to 4 carbon atoms (wherein alkyl, alkenyl, or alkynyl is substituted by one or two Ar (wherein Ar is defined as the same as the above), and may be further substituted by a group selected from xe2x80x94OH, xe2x80x94CF3, and cycloalkyl having 3 to 8 carbon atoms)).
Step J-1 is the step of alkylating amide. This step is carried out by reacting compound 40 with a base, and then reacting the product with the following compound:
Br(CH2)sOTBS
or
Cl(CH2 )sOTBS
(wherein s and TBS are defined as the same as the above). As the base, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step J-2 is the step of removing a TBS group of compound 68. This step is carried out by treating compound 68 with fluorine ion. As a fluorine ion source, tetrabutylammonium fluoride, potassium fluoride, hydrofluoric acid, or the like is used. As a solvent, tetrahydrofuran, dimethoxyethane, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step J-3 is the step of converting a hydroxyl group of compound 69 to a leaving group. This step is carried out by the same method as step A-2.
Step J-4 is the step of converting a hydroxyl group of compound 70 to azide. This step is carried out by treating compound 70 with sodium azide. As a solvent, DMF, tetrahydrofuran, dimethoxyethane, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step J-5 is the step of reducing compound 71. This step is carried out by the same method as step I-5.
Step J-6 is the step of acylating compound 72. This step is carried out by reacting compound 72 with a corresponding carboxylic acid in the presence of a condensing agent. As the condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-cyclohexyl-3-(2-morpholynoethyl)carbodiimide metho-p-toluenesufonate, or the like is preferably used. As a solvent, acetonitrile, DMF, tetrahydrofuran, dimethoxyethane, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours. Similarly to step E-1, this step can also be carried out by reacting compound 72 with an acid chloride or acid anhydride in the presence of an appropriate base.
Step J-7 is the step of removing a tetrahydropyranyl group of compound 73. This step is carried out by the same method as step F-7.
Step J-8 is the step of reducing amide of compound 74. This step is carried out by the same method as step C-5.
Step J-9 is the step of introducing an ester unit into compound 75. This step is carried out by the same method as step A-1.
Step J-10 is the step of ester hydrolysis of compound 76. This step is carried out by the same method as step A-4.
Of the compounds of the present invention, compounds in which A1 is xe2x80x94CH2xe2x80x94, A2 is xe2x80x94(Nxe2x80x94)xe2x80x94CH2xe2x80x94, A3 is straight chain alkylene having 1 to 4 carbon atoms, R3 is hydrogen, and X is xe2x80x94Oxe2x80x94 can be produced by production method K. 
(wherein R2, m, n, R11, R12, R13, R15, and q are defined as the same as the above).
Step K-1 is the step of producing amide by rearrangement reaction of tetralone. This step is carried. out by reacting compound 78 with sodium azide in trifluoroacetic acid. The reaction temperature is xe2x88x9220xc2x0 C. to the reflux temperature of a solvent. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step K-2 is the step of protecting a phenolic hydroxyl group by an acetyl group. This step is carried out by reacting with acetic anhydride or acetyl chloride in the presence of an appropriate base. As the base, pyridine, triethylamine, or the like is used. As a solvent, THF, DME, methylene chloride, or the like is used, and pyridine may be used as the solvent. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step K-3 is the step of introducing an ester unit into amide. This step is carried out by reacting compound 80 with the following compound in the presence of an appropriate base:
Br(CH2)qCOOR15
(wherein R15 and q are defined as the same as the above). As the base, potassium carbonate, potassium t-butoxide, potassium hydroxide, sodium hydroxide, sodium hydride, or the like is used. As a solvent, methanol, ethanol, DMF, DMSO, THF, DME, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step K-4 is the step of reducing ester and amidoe and removing an acetyl group at the same time. This step is carried out by reacting compound 81 with lithium aluminum hydride. As a solvent, THF, DME, ether, or the like is used. The reaction temperature is xe2x88x9240xc2x0 C. to the reflux temperature of the solvent. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step K-5 is the step of introducing an ester unit into compound 82. This step is carried out by the same method as step A-1.
Step K-6 is the step of converting a hydroxyl group of compound 83 to a leaving group. This step is carried out by the same method as step A-2.
Step K-7 is the step of thioetherifying compound 84. This step is carried out by the same method as step A-3.
Step K-8 is the step of ester hydrolysis of compound 85. This step is carried out by the same method as step A-4.
Step K-9 is the step of forming a salt of compound 86. This step is carried out by the same method as step A-5.
Of the starting raw materials of the production method E, compounds in which A1 is xe2x80x94CH2xe2x80x94, m is 1, and R3 is hydrogen can be produced by production method L. 
(wherein TBS represents a t-butyldimethylsilyl group).
Step L-1 is the step of protecting a hydroxyl group of quinoline by a t-butyldimethylsilyl group. This step is carried out by reacting compound 88 with t-butyldimethylsilylchloride in the presence of an appropriate base. As the base, imidazole is preferably used. As a solvent, DMF, THF, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 80 hours, and is usually 5 minutes to 30 hours.
Step L-2 is the step of reducing quinoline to tetrahydroquinoline, and performed under conventional conditions for hydrogenation. This step is carried out by using a catalyst such as palladium-carbon, Raney nickel, or the like under a hydrogen atmosphere at a pressure of 1 to 10 atm. As a solvent, methanol, ethanol, THF, ethyl acetate, benzene, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Of the compounds of the present invention, compounds in which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(CHxe2x80x94)xe2x80x94, A3 is xe2x80x94CH2CH2xe2x80x94, A4 is xe2x80x94Sxe2x80x94, R3 is hydrogen, X is xe2x80x94Oxe2x80x94, and m is 1 can be produced by production method M.
Step M-1 is the step of reducing benzofuran to dihydrobenzofuran. This step is carried out by using a catalyst such as palladium-carbon, Raney nickel, or the like under a hydrogen atmosphere at a pressure of 1 to 10 atm., and reaction is accelerated by adding an acid such as acetic acid, hydrochloric acid, or the like. As a solvent, methanol, ethanol, THF, ethyl acetate, benzene, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 50xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours.
Step M-2 is the step of thioetherifying compound 92. This step is carried out by the same method as step A-3.
Step M-3 is the step of ester hydrolysis of compound 93. This step is carried out by the same method as step A-4.
Step M-4 is the step of forming a salt of compound 94. This step is carried out by the same method as step A-5. 
(wherein R2, n, R11 and R13 are defined as the same as the above).
Of the compounds of the present invention, optically active compounds in which A1 is xe2x80x94Oxe2x80x94, A2 is xe2x80x94(CHxe2x80x94)xe2x80x94, A3 is xe2x80x94CH2CH2xe2x80x94, A4 is xe2x80x94Sxe2x80x94, R3 is hydrogen, X is xe2x80x94Oxe2x80x94, and m is 1 can be produced by production method N. 
(wherein R2, n, R11, R12, R13 and R14 are defined as the same as the above, and R18 represents an optically active amine cation).
Step N-1 is the step of introducing an ester unit into a phenolic hydroxyl group of compound 96. This step is carried out by the same method as step A-1.
Step N-2 is the step of reducing benzofuran of compound 97 to dihydrobenzofuran. This step is carried out by the same method as step M-1.
Step N-3 is the step of ester hydrolysis of compound 98. This step is carried out by the same method as step A-4.
Step N-4 is the step of optical resolution of compound 99, comprising a salt formation step and a resolution step. The salt formation step is carried out by reacting compound 99 with an optically active amine. As the optically active amine, 1-(1-naphthyl)ethylamine, 2-(benzylamino)cyclohexane methanol, cinchonine, or the like is preferably used. As a solvent, water, methanol, ethanol, tetrahydrofuran, ethyl acetate, or the like is used. The reaction temperature is selected from xe2x88x9250 to 150xc2x0 C., and is preferably 0 to 80xc2x0 C. The reaction time is 1 minute to 120 hours, and is usually 1 minute to 30 hours. The resolution step is carried out by dissolving an optically active amine salt of compound 99 under heating, and then standing it to cool. Crystallization may be accelerated by adding a seed crystal. As a solvent, water, methanol, ethanol, tetrahydrofuran, ethyl acetate, or the like is used.
N-5 is the step of esterifying compound 100. This step is carried out by refluxing compound 100 with alcohol under acidic conditions. As an acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or the like is used. As a solvent, benzene, toluene, or the like is used, and alcohol may be used as the solvent. Furthermore, a dehydrating agent may be added, or a dehydrating device such as Dean-stark or the like may be used. The reaction temperature is selected from 0 to 150xc2x0 C., and reaction is preferably effected under reflux conditions of the solvent. The reaction time is 1 minute to 120 hours, and is usually 5 minutes to 50 hours
Step N-6 is the step of converting a hydroxyl group of compound 101 to a leaving group. This step is carried out by the same method as step A-2.
Step N-7 is the step of thioetherifying compound 102. This step is carried out by the same method as step A-3.
Step N-8 is the step of ester hydrolysis of compound 103. This step is carried out by the same method as step A-4.
Step N-9 is the step of forming a salt of compound 104. This step is carried out by the same method as step A-5.
With the compounds of the present invention having asymmetric carbons, the formula represents d, l and dl isomers. Each of the steps can be applied to the d, l and dl isomers in the same manner.
In producing dl isomers of the compounds of the present invention, compounds represented by formula (I), which are obtained in a racemic modification, can easily be separated into d and l isomers by an optically active column chromatography technique.
The compounds of the present invention have the strong TXA2 receptor antagonistic action and PGI2 receptor agonistic action, and thus have pharmacological actions such as the platelet aggregation inhibiting action, vascular contraction inhibiting action, bronchial contraction inhibiting action, etc. Therefore, these compounds are effective to treat or prevent diseases such as hypertension, thrombosis, ischemic heart diseases (myocardial infarction, angina pectoris, thrombogenesis after PTCA, etc.), cerebral circulatory disorders (cerebral infarction, transient cerebral ischemic attack, etc.), peripheral circulatory disorders (Buerger""s disease, Raynaud""s disease, Behcet""s disease, thrombotic thrombocytopetic purpura, hepatic disorders, renal disorders, etc.), arteriosclerosis, platelet functional disorder concurrent with diabetes, hyperlipidemia, nephritis, asthma, allergic diseases, etc.
For this purpose, the compounds of the present invention can be generally administered by intravenous injection, intraarterial injection, intramuscular injection, percutaneous administration, subcutaneous administration, or oral administration. In general oral or rectal administration, the compound is administered 1 to 4 times a day at a dose of 1 xcexcg/kg/day to 100 mg/kg/day. In intravenous infusion or intraarterial injection, the compound is administered at a dose of 1 ng/kg/min to 1 mg/kg/min to obtain good results. In general intravenous injection, intraarterial injection, intramuscular injection, or subcutaneous administration, the compound is administered 1 to 4 times a day at a dose of 0.1 xcexcg/kg/day to 100 mg/kg/day. In these administrations, a dose is selected from the above-described ranges in consideration of the age, sexuality, and conditions of a patient, and the times of administration of the compound, etc.
The compounds of the present invention can be orally administered in a solid form containing starch, lactose, sucrose, glucose, crystalline cellulose, an excipient such as a type of clay, a colorant, a lubricant, a binder, a disintegrant, and a coating agent. The compounds of the present invention may be parenterally administered in the form of a sterilized solution, and may also contain other solutes such as a tonicity agent such as sodium chloride, glucose, or the like, a PH regulator, and solution adjuvant such as cyclodextrin or the like. The compounds of the present invention have stability in chemical structure, and thus cause no difficulties in formulation, thereby permitting a variety of administration methods such as oral formulations (tablets, powder, and granules), various injections, suppositories, ointments, lotions, etc.